The growing demand for chiral non-racemic compounds and drugs in the pharmaceutical industry has created a formidable synthetic challenge for chemists to find cost-effective and highly stereoselective means to assemble these molecules. Of the various methods available for the preparation of enantiomerically pure compounds, asymmetric catalytic processes are the most attractive. Over the past several decades, the main body of research in catalysis has been focused on transition metal-based organometallic catalysts and significant progress has been made. Surprisingly, however, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts (organocatalysts) despite their enormous potential in asymmetric transformations and widespread availability in optically pure forms.
A chiral molecule is one that is not superimposable on its mirror image. Often referred to as ‘handedness,” (in fact the term “chirality” derives from the Greek word for “hand”) since the property can be demonstrated by examining one's hands, which are mirror images of each other, but which are not superimposable one on the other. A chiral molecule is also observable for having the property of rotating the plane of polarization of plane-polarized monochromatic light passed through it—a phenomenon called “optical activity.” Pure solutions of a single stereoisomer (the chiral molecule and its mirror image are called “stereoisomers” or “enantiomers”) will rotate the plane of plane polarized light in one direction, and the other enantiomer will rotate polarized light the same number of degrees, but in the opposite direction. For this reason, stereoisomers are often called “optical isomers.” A solution that contains an equal mixture of the two optical isomers (a “racemic” mixture) will not change the plane of plane polarized light, because the effects of the two isomers cancel each other out. Pairs of stereoisomers are sometimes indistinguishable one from another in chemical reactions, but can be distinguished by examining a physical property (usually optical) of the molecule.
It has long been known, particularly in the pharmaceutical industry, that often one enantiomer is more effective in a reaction (or in a therapeutic treatment) than its mirror-image counterpart. In fact, in one well documented case of the importance of chirality, the use of a racemic mixture of thalidomide in pregnant women caused severe birth defects in their children. It was determined that one enantiomer was a powerful sedative while the other was toxic. As a result, obtaining a substantially pure form of a single enantiomer is often very desirable.
Given the Laws of Thermodynamics, this proves initially difficult. The left- and right-handed forms have identical free energy (G), so the free energy difference (ΔG) is zero. The equilibrium constant for any reaction (K) is the equilibrium ratio of the concentration of products to reactants. The relationship between these quantities at any Kelvin temperature (T) is given by the standard equation:K=exp(−ΔG/RT)
wherein R is the universal gas constant (Avogadro's number×Boltzmann's constant k)=8.314 J/K·mol.
For the reaction of changing left-handed to right-handed amino acids (L→R), or the reverse (R→L), ΔG=0, so K=1. That is, the reaction reaches equilibrium when the concentrations of R and L are equal; that is, a racemate is produced.
For separation of or “resolving” a racemate (i.e., separate the two enantiomers), another homochiral substance is usually introduced. The idea is that right-handed and left-handed substances have identical properties, except when interacting with other chiral phenomena. The analogy is that our left and right hands grip an achiral (non-chiral) object like a stick equally, but they fit differently into a chiral object like a left-handed glove. Thus to resolve a racemate, an organic chemist will usually use a ready-made homochiral substance from a living organism. The reaction products of the R and L enantiomers with an exclusively right-handed substance R′, that is R-R′ and L-R′ (called diastereomers), are not mirror images. So they have different physical properties, e.g. solubility in water, and thus they can be separated.
This often requires a homo-chiral substance to separate the enantiomers and the ability to separate the substance from the desired enantiomer. While available for separation of some chiral substances, such substances are certainly not readily available for all. Chemists have tried other ways to reach their goal of substantially pure enantiomers, including asymmetric synthesis, wherein only one enantiomer is produced in synthesis of the compound, thereby eliminating the need to resolve a racemate.
In particular, asymmetric synthesis of optically active natural and unnatural α-amino acids has been of long-standing interest to organic chemists since these substances are versatile synthetic building blocks for the preparation of an assortment of biologically important molecules. In this regard, the enantioselective Mannich-type reaction of an enolate or enolate equivalent with α-imino ester constitutes a powerful approach to the synthesis of novel functionalized γ-keto-α-amino acid derivatives. S. E. Denmark, O. J.-C. Nicaise In Comprehensive Asymmetric Catalysis, (Eds.; E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, pp 926; b) D. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110, 1096-1122; D. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Over the past few years, catalytic, enantioselective versions of this process have received great attention with emphasis being given to the development of organometallic catalysis. S. E. Denmark, O. J.-C. Nicaise In Comprehensive Asymmetric Catalysis, (Eds.; E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, pp 926; b) D. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110, 1096-1122; D. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 37, 1044-1070; H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119, 7153-7154; b) S. Kobayashi, T. Hamada, K. Manabe, J. Am. Chem. Soc. 2002, 124, 5640-5641; c) H. Ishitani, S. Ueno, S. Kobayashi, J. Am. Chem. Soc. 2000, 122, 8180-8186; E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120, 2474-2475; b) A. Fujii, E. Hagiwara, M. Sodeoka, J. Am. Chem. Soc. 1999, 121, 545-556; D. Ferraris, B. Young, T. Dudding, T. Lectka, J. Am. Chem. Soc. 1998, 120, 2474-2475; b) D. Ferraris, B. Young, C. Cox, T. Dudding, W. J. Drury, III, L. Ryzhkov, T. Taggi, T. Lectka, J. Am. Chem. Soc. 2002, 124, 67-77.
However, these metal-based catalysis methods rely on the use of pre-formed enolates or enolate equivalents. An effective, atom-economic asymmetric version of this reaction, employing unmodified carbonyl compounds would be more attractive from a synthesis standpoint. The examples of such reactions catalyzed by organometallic-based chiral catalysts have been described by Shibasaki, Trost and Jørgensen. S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron Lett. 1999, 40, 307-310; B. M. Trost, L. M. Terrell, J. Am. Chem. Soc. 2003, 125, 338-339; K. Juhl, N. Gathergood, K. A. Jørgensen, Angew. Chem. 2001, 113, 3083-3085; K. Juhl, N. Gathergood, K. A. Jørgensen, Angew. Chem. Int. Ed. 2001, 40, 2995-2997.
The development of metal-free organo-catalysts has emerged as a new frontier in asymmetric catalysis, pioneered by List, Barbas III, and MacMillan. P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840-3864; P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40, 3726-3748; b) a review of proline catalyzed reactions: B. List, Tetrahedron 2002, 58, 5573-5590; B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122, 2395-2396; K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243-4244.
Several catalytic systems including L-proline, peptides and small organic molecules have been reported for the Mannich reactions. B. List J. Am. Chem. Soc. 2000, 122, 9336-9337; B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124, 827-833; Y. Hayashi, W. Tsuboi, M. Shoji, N. Suzuki, J. Am. Chem. Soc. 2003, 125, 11208-11209; Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. 2003, 115, 3805-3808; Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. Ed. Engl. 2003, 42, 3677-3680; A. Córdova, W. Notz, G. Zhong, J. M. Betancort, C. F. Barbas III, J. Am. Chem. Soc. 2002, 124, 1842-1843; b) A. Córdova, S. Watanabe, F. Tanaka, W. Notz, C. F., Barbas III, J. Am. Chem. Soc. 2002, 124, 1866-1867; c) A. Córdova, C. F. Barbas III, Tetrahedron Lett. 2003, 44, 1923-1926; P. Vachal, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012-10013; b) A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964-12965. Only the L-proline catalyzed process described by Barbas III (referenced above) and his co-workers promotes direct Mannich-type reactions of ketones and aldehydes with α-imino esters.
Compared with traditional metal-ligand complex catalysts, it is surprisingly found that metal-free organo-catalysts are less expensive, benign to the environment, easy to prepare and handle, and are air-stable, and non-sensitive to moisture. Therefore, the field would be greatly enhanced with the development of novel metal-free organo-catalysts which reduce time, effort, and amount of reactant necessary to arrive at a single enantiomer product. In turn, industries such as the pharmaceutical industry which require such purified forms can reduce the cost of and improve the quality of their ultimate product.
One of the important Michael addition reactions is the addition of nucleophiles to electron deficient nitroalkenes.[1,2] Because the versatile nitro functionality can be easily transformed into amine, nitrile oxide, ketone or carboxylic acid, hydrogen, etc.,[2b] various enantioselective processes have been reported mainly by employing stoichiometric amounts of enantiopure additives.[3] And also the catalytic asymmetric versions of this reaction were achieved by using chiral metal-ligand complexes.[4] Recently, we and others have developed more environmental friendly metal-free organocatalysts to catalyze efficient asymmetric Michael addition reactions.[5-7] In these approaches, the donors employed in these processes have been restricted to aldehydes and ketones,[5] malonate esters,[6] and ketoesters.[7] Herein, we wish to report a novel type of organocatalysts, bifunctional binaphthyl-derived amine thioureas, which have been first demonstrated for catalyzing highly enantioselective Michael addition reactions using 1,3-diketones as donors. Furthermore, in the preliminary study, we have demonstrated that the Michael adducts can be readily converted to synthetically and biologically useful building blocks α-substituted-β-amino acids.
In the past few years, the utilization of chiral ureas/thioureas has emerged as a viable strategy in the design of efficient organocatalysts for asymmetric organic transformations.[6, 8-11] Notable examples include Jacobsen's ureas/thioureas for catalyzing a variety of reactions[9] and Takemoto's amine thioureas for Michael addition and aza-Henry reactions.[6a,b, 10] It is noted that both catalyst systems are built upon the trans-cyclohexane diamine scaffold. More recently, cinchona alkaloids-based thioureas have been employed for Michael addition reaction as well.[11] However, thioureas derived from another important “privileged” structure binaphthyl have not been reported yet.[12] We envisioned that the inclusion of a thiourea and an amine moiety into the scaffold could lead to a new class of bifunctional organocatalysts, which would provide high catalytic activity and enantioselectivity toward organic reactions. The results from this investigation disclosed that a newly designed organocatalyst VII (see below) displayed remarkably catalytic activity (1 mol % catalyst loading) on the processes with achieving excellent levels of enantioselectivities (up to 97% ee).
Separately, in recent years, the Morita-Baylis-Hillman (MBH) reaction, which involves forming new C—C bonds and generating highly functionalized chiral allylic alcohols, has received considerable interest in organic synthesis.1a Therefore, not surprisingly, a considerable amount of effort has been devoted to the development of catalytic, enantioselective versions of the processes. However, discovering catalytic systems for asymmetric MBH reactions has proven to be a synthetic challenge, and to date, a very limited number of successful chiral catalysts have been demonstrated for this process.2a,3a Among them, notably, the research groups of Hatakeyama2aa and Chen2ab respectively, have developed quinidine-based chiral amines and chiral Lewis acids as catalysts for promoting addition of acrylates to aldehydes. Schaus et al2ac reported an elegant BINOL derived Brønsted acid, and Shi2ad and Miller2ae independently used an amino acid L-proline as organocatalyst for the asymmetric MBH reactions of α, β-unsaturated ketones with aldehydes. However, both cases require adding a Lewis base for facilitating the reactions. From an operational and atom-economic standpoint, the utilization of bifunctional catalysts is highly desirable, but such catalysts have not been developed yet. Moreover, generally, a bifunctional catalyst can activate two functional groups in their substrates via synergistic interactions and, thus, specifically control transition state structure, leading to higher catalytic activity and better enantioselectivity.4a In this communication, we wish to first report a novel type of bifunctional organocatalyst, the chiral amine-thiourea for catalyzing highly enantioselective MBH reactions.